The Bcr-Abl kinase inhibitor INNO-406 induces autophagy and different modes of cell death execution in Bcr-Abl-positive leukemias

• Published in: Cell death and differentiation Vol. 15; no. 11; pp. 1712 - 1722
• Main Authors: Kamitsuji, Y, Kuroda, J, Kimura, S, Toyokuni, S, Watanabe, K, Ashihara, E, Tanaka, H, Yui, Y, Watanabe, M, Matsubara, H, Mizushima, Y, Hiraumi, Y, Kawata, E, Yoshikawa, T, Maekawa, T, Nakahata, T, Adachi, S
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.11.2008; Nature Publishing Group
• Subjects: Animals; Apoptosis; Apoptosomes - drug effects; Apoptosomes - metabolism; Autophagy; Autophagy - drug effects; Biochemistry; Biology; Biomedical and Life Sciences; Caspases - metabolism; Cell Biology; Cell Cycle Analysis; Cell death; Cell Line, Tumor; Chloroquine - pharmacology; Cytochrome; Cytoprotection - drug effects; Disease Models, Animal; Enzyme Activation - drug effects; Fusion Proteins, bcr-abl - antagonists & inhibitors; Hematology; Kinases; Leukemia; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - enzymology; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - pathology; Life Sciences; Male; Medicine; Mice; Mice, SCID; Microscopy; Oncology; original-paper; Pediatrics; Protein Kinase Inhibitors - pharmacology; Pyrimidines - pharmacology; Stem Cells; Xenograft Model Antitumor Assays; Japan; apoptosis; Bcr-Abl; autophagy; INNO-406; caspase
• ISSN: 1350-9047; 1476-5403
• DOI: 10.1038/cdd.2008.107

Bcr-Abl tyrosine kinase (TK) inhibitors are promising therapeutic agents for Bcr-Abl-positive (Bcr-Abl + ) leukemias. Although they are known to promote caspase-mediated apoptosis, it remains unclear whether caspase-independent cell death-inducing mechanisms are also triggered. Here we demonstrated that INNO-406, a second-generation Bcr-Abl TK inhibitor, induces programmed cell death (PCD) in chronic myelogenous leukemia (CML) cell lines through both caspase-mediated and caspase-independent pathways. The latter pathways include caspase-independent apoptosis (CIA) and necrosis-like cell death (CIND), and the cell lines varied regarding which mechanism was elicited upon INNO-406 treatment. We also observed that the propensity toward CIA or CIND in cells was strongly associated with cellular dependency on apoptosome-mediated caspase activity. Cells that undergo CIND have a high apoptosome activity potential whereas cells that undergo CIA tend to have a lower potential. Moreover, we found that INNO-406 promotes autophagy. When autophagy was inhibited with chloroquine or gene knockdown of beclin1 by shRNA, INNO-406-induced cell death was enhanced, which indicates that the autophagic response of the tumor cells is protective. These findings suggest new insights into the biology and therapy of Bcr-Abl + leukemias.